Chronic pain is a global issue, and current treatments often involve opioids, which come with risks of addiction and overdose.
Finding non-addictive alternatives could transform pain management. Recent research focusing on the human protein responsible for cold sensations brings us closer to developing pain medications that don’t affect body temperature and aren’t addictive.
Published in Science Advances on June 21, a study led by Wade Van Horn, a professor at Arizona State University, has brought to light new insights into the human protein TRPM8 (transient receptor potential melastatin 8), which regulates cold and menthol sensing. Their research reveals that this protein initially functioned as a chemical sensor before evolving into a cold sensor.
“Understanding how to separate chemical sensing of cold from actual cold sensing could lead to drugs with minimal side effects,” said Van Horn, whose research focuses on membrane proteins relevant to human health and diseases. “By exploring the evolutionary history of TRPM8, we aim to develop better drugs that provide relief without the harmful side effects associated with current painkillers.”
TRPM8 is activated when one touches a cold surface like a metal desk, causing a cool sensation. In contrast, for cancer patients undergoing certain chemotherapies, this touch can be painful. TRPM8 is also implicated in various types of pain, including chronic neuropathic and inflammatory pain.
By understanding the distinction between chemical and physical cold sensing, scientists can target pain relief without triggering the unwanted temperature regulation side effects observed in clinical trials involving TRPM8 for pain management.
In their study, the research team employed ancestral sequence reconstruction, akin to a protein time machine, to trace the evolutionary lineage of TRPM8. By comparing current protein sequences with predicted sequences of ancient ancestors, such as primates and mammals, they uncovered the changes that have occurred in TRPM8 over millions of years.
Through computational methods that resurrected ancestral forms of TRPM8, researchers gained insights into how this protein has evolved and identified critical regions involved in temperature sensing, paving the way for further experiments.
“Our comparative analysis of ancestral and human TRPM8, in combination with experimental data, will help pinpoint crucial temperature-sensing sites for future testing,” explained Banu Ozkan, a professor at ASU’s Department of Physics and a key contributor to the study.
The team then introduced these ancestral TRPM8 proteins into human cells and studied them using various cellular and electrophysiology techniques.
“Studying ancestral proteins allows us to focus on the lineage of interest, such as human TRPM8, addressing concerns in drug development arising from differences between species like mice and humans,” noted Dustin Luu, the study’s first author, who is a doctoral alumnus of ASU School of Molecular Sciences and a postdoctoral fellow at ASU’s Biodesign Center for Personalized Diagnostics.
Luu highlighted, “Our discovery that the sensing of menthol preceded cold sensing significantly indicates separate activation modes that can be untangled with further research, potentially leading to new pain treatments without the complications in temperature sensing and regulation that have hindered TRPM8-targeted clinical trials.”
As scientific exploration progresses in unraveling our biological processes, studies like this demonstrate how evolutionary biology and modern pharmacology can collaborate to address critical medical needs and enhance the quality of life for individuals dealing with chronic pain.
